Specific therapy for inflammatory bowel disease (IBD) would, if possible, obviously be directed at the initiating event. There is strong reason to believe that the initiating and/or perpetuating event in IBD is related to the host's response to an antigen(s). However, the putative antigen(s), and their tissue distribution, that are the targets of the pathologic immunologic process in IBD are, at present, unknown. In the absence of this knowledge, therapies directed at these diseases have been, and must remain, somewhat nonspecific for many aspects of the inflammatory process. Since T cells are the primary orchestrators of the host's response to antigens, this suggests that T cells play an important either primary or supportive role in the pathogenesis of IBD, both ulcerative colitis (UC) and Crohn's disease (CD). This hypothesis is indirectly supported by evidence of T cell activation in IBD and the association of IBD with specific major histocompatibility complex (MHC) haplotypes. Because each T cell recognizes a distinct antigen via its own unique T cell receptor (TCR), knowledge of specific antigens in IBD may be obtained indirectly through an examination of the TCRs on T cells. Normally, an individual harbors a large number of T cell clones each with its own distinct, or clonotypic, receptor for the recognition of unforseen foreign antigenic events. In the context of a specific antigenic exposure, T cell clones specific for that antigen will respond and expand in number. Therefore, as a result of either constant or recurrent antigenic exposure or an inappropriate response to a self antigen, excessive expansion of the responsive T cell clone would be observed. Thus, excessive clonal expansions of T cells can be used as an indirect indication of the presence of an antigen that is perceived as foreign as is observed in other infectious and autoimmune diseases. In diseases in which the antigen is unknown, identification of a T cell clone can be used to gain knowledge about the specific antigen(s) which originally induced its expansion. In view of the systemic nature of IBD and preliminary studies which are consistent with the existence of distinct T cell clonal expansions within the intestine and peripheral blood of IBD. the major goal of this grant is to use polymerase chain reaction and cellular cloning techniques to identify candidate pathogenic T cell clones based upon their: (1) activated phenotype; (2) expansion relative to other T cell clones; (3) presence in multiple tissues; (4) presence over an extended timeframe, and; (5) correlation with disease activity.